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Hemolytic Anemia in children Hemolytic Anemia in children

Hematology-Oncology Division

Child Health Departement Child Health Departement Sumatera Utara University

Hemolytic anemia

Premature destruction of erythrocyte or red blood

Premature destruction of erythrocyte or red blood cells (RBC)

Anemia: rate of destruction exceeds the capacity of

the marrow to produce RBC

RBC survival is shortened, RBC count

falls erythropoetin is increased falls,erythropoetin is increased

Classification

1.Cellular:

There are four main 1.Cellular:

• Intrinsic

abnormalities of the There are four main types of Inherited Hemolytic anemia: membrane

• Enzymes

1.Hemoglobinopathies

• Hemoglobin

Virtually: Inherited 2.Thalassemia 3.Enzyme defects 4.Membrane defects

2.Extracellular

Acqiured hemolytic 2.Extracellular

• antibodies
• mechanical factors

Acqiured hemolytic anemia Immune:

• plasma factors

Virtually : Acquired

• Direct complement

mediated y q

• Autoimmune HA

Warm ab IgG Cold ab IgM Cold ab IgM

….Classification

2.Non-Immune : 6.Oxydative drugs or 1.Mechanical trauma: HUS TTP DIC 6.Oxydative drugs or chemical 7.Severe burns HUS, TTP,DIC 2.Thermal injury 3.Acanthocytosis 8.Venom 9.Infection: y 4.Severe hypophosphatemia 5 Wilson’s disease Malaria,babesiasis, bartonellosis,Trypanos

• miasis gram

5.Wilson s disease, Copper poisoning

• miasis, gram

negative/positive

Table 3. Some common drugs and chemicals g that can induce hemolytic anemia

Acetanilide Doxorubicin Niridazole Nitrofurantoin Furazolidone Methylene blue Phenazopyridine Primaquine Nalidixic acid Sulfamethoxazole

N Eng J Med 1991; 324;171

Mayor catagory

1.Immune mediated (alloimmune or

1.Immune mediated (alloimmune or autoimmune)

2.Membrane defects (spherocytosis,

( p y , elliptocytosis)

3.Enzym defects ( G6PD deficiency ,

pyruvate kinase deficiency)

4.Hemoglobin defects ( sickle cell disease,

th l i ) thalassemia )

Approach to diagnosis

1 Clinical features suggesting hemolytic

• 1. Clinical features suggesting hemolytic

disease

2 Laboratory

• 2. Laboratory
• 3. Special hematologic investigation

Clinical features suggest a hemolytic process

1 Ethnic factors

• 1. Ethnic factors
• 2. Age factors

3 History of anemia jaundice gallstones in

• 3. History of anemia,jaundice.gallstones in

family 4 P i t t t i i t d

• 4. Persistent or recurrent anemia associated

reticulocytosis 5 A i i t h ti i

• 5. Anemia unresponsive to hematinics

6

Intermitent or persistent indirect

• 6. Intermitent or persistent indirect

hyperbilirubinemia

7

Splenomegaly

• 7. Splenomegaly
• 8. Hemoglobinuria

9 M lti l ll t

• 9. Multiple gallstones
• 10. Chronic leg ulcers
• 11. Exposure to certain drugs

Inherited Hemolytic Anemia

A.Red cell membrane defect

A.1. Hereditary Spherocytosis

Essentials of diagnosis & typical features

Anemia and jaundice Anemia and jaundice Splenomegaly Positive family history of anemia, jaundice

• r gallstones.

Spherocytosis with ↑reticulosytes ↑Osmotic fragilility ↑Osmotic fragilility Negative coombs test

A 2 Hereditary Elliptocytosis A.2. Hereditary Elliptocytosis Autosomal dominant inheritance Most are asymptomatic Elevated reticulosyte Jaundice and splenomegaly Jaundice and splenomegaly

No treatment is indicated :

• folate suplementation
• splenectomy

• B. Enzyme Deficiencies

B.1. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency (G6PD) Deficiency

Essentials of diagnosis & typical features

• Symptoms develop 24-48 hr after ingested a

substanceshas oxidant properties, such as aspirin, sulfonamides, and antimalarias

• African Mediterranean or Asian ancestry
• African, Mediterranean or Asian ancestry
• Neonatal hyperbilirubinemia
• Sporadic hemolysis infection, oxidant drugs

fava beans

• X- linked inheritance.

Acute : precipitous fall Hb + Ht

• Acute : precipitous fall Hb + Ht
• Heinz bodies in RBCs’ unstained/supravital

• Polychromatophilic cells, reticulocytosis
• Enzymes activity < 10% normal
• Reduction of enzymes activity more extreme in

Americans of European descent and in Asians than Americans of Africans descent than Americans of Africans descent

• Screening tests : decoloration of methylene blue,

reduction of methemoglobin, or fluorescence of reduction of methemoglobin, or fluorescence of NADPH.

• After hemolytic episode reticulocytes and young

RBCs predominate

• Dx suspected: G6PD activity is within low normal

i th f hi h ti l t range in the presence of a high reticulocyte count

Acquired Hemolytic Anemia

1 Microangiopathic Hemolytic Anemia 1.Microangiopathic Hemolytic Anemia Hallmark: - schistocytes ( red cell fragments)

• n peripheral blood smear analysis
• n peripheral blood smear analysis.

Infection and sepsis microagiopathy , t ll d fib i i RBC uncontrolled fibrinogenesis RBC destruction S RBC d t ti th b t i Severe RBC destruction , thrombocytopenia, coagulation factor consumption, DIC

Hemolytic Uremic Syndrome ( HUS) Hemolytic Uremic Syndrome ( HUS)

• Microangiopathic
• Decreased von Willebrand protease

Decreased von Willebrand protease

• Infection with enteric bacteria: Escherichia

coli O157:H7 Thrombotic thrombocytopenic purpura

• Decreased von Willebrand protease

Decreased von Willebrand protease

• HUS + neurologic symptoms, inherited or

acquired q

• 2. Immune-Mediated Hemolytic Anemias
• 2. Immune Mediated Hemolytic Anemias
• Antibody againts one or more antigenson the

surface of RBC opsonization premature destruction: - erythocytes RES

• complement-mediated lysis of

RBC in the bloodstream

• Antibodies come from patients: AIHA
• Antibodies come from another source : Alloimmune

hemolytic anemia Hemolytic disease of the newborn newborn

2.1.Autoimmune Hemolytic Anemia (AIHA) (AIHA)

History: previous viral or viral like illness History: previous viral or viral like illness,

fatigue, pallor

Ussually sudden severe anemia Ussually sudden, severe anemia Dark urine:acute intravascular

hemolysiscomplement mediated red cell hemolysiscomplement mediated red cell lysis

Jaundice sclerae pruritus Jaundice sclerae,pruritus Mild splenomegaly

Autoimmune Hemolytic Anemia

2.1.1.Intravascular hemolysis

Complement mediated,IgM,complement-

p , g , p fixing IgG direct against RBC antigen jaundice (hyperbilirubinemia) , LDH , low haptoglobin

2.1.2.Extravascular hemolysis

Mediated by IgG Mediated by IgG NO increase LDH , bilirubin

RBC destroyed in RES plasma

RBC destroyed in RES, plasma Laboratory evaluation

• Moderate to severe anemia
• Brisk reticulocytosis
• Spherocytosis,polychromasia,RBC clumping

p y ,p y , p g

• Hemoglobinuria

Hemoglobinuria

• Direct Coombs test (antibody bound to the

patient’s RBC) : (+) patient s RBC) : (+)

• Indirect Coombs test (test for free

antierythrocyte antibody in the patient’s antierythrocyte antibody in the patient s serum

Primary AIHA :

1 Warm-reactive AIHA 1.Warm reactive AIHA Usually : IgG binds RBC antigen at 37oC 2 Paroxysmal Cold Hemoglobinuria 2.Paroxysmal Cold Hemoglobinuria 3.Cold Agglutinin Disease: Usually IgM binds erythrocyte antigens (typically red cell surface polysaccharide) d fi l t t t b l 37oC and fixes complement at temp.below 37oC

Classification of autoimmune hemolytic anemia

Warm-reactive autoantibodies primary Paroxysmal cold hemoglobinuria (PCH) Secondary Lymphoproliferative disorders Autoimmune disorders (SLE) Tertiary syphillis Post-viral infection Infectious mononucleosis Evan’s syndrome HIV associated Drug induced hemolytic anemia Hapten mediated (PCN) Immune complex type (quinidine quinine) Cold-reactive antibodies Idiopathic (cold aglutinin disease) (quinidine, quinine) True autoimmune anti-RBC type ( methyldopa) Metabolite driven d sease) secondary Atypical or mycoplasma pneumonia I f i l i Metabolite driven Infectious mononucleosis Lymphoproliferative disorders

Treatment of Acquired Hemolytic Anemia

Methyl-prednisolone 1 to 2 mg/Kg/day/iv Methyl prednisolone 1 to 2 mg/Kg/day/iv

every 6 hours should be initiated promptly.Response (+) :increasingly stable p p y p ( ) g y Hb,decreasing reticulocytosis,diminishing transfusion.After stabilization,prednisone 1 to p 2 md /Kg /day can be substituted for methylprednisolone gradually tapered over several weeks to months

IV Immunoglobulin IV Immunoglobulin Exchange transfusion/Plasmapheresis :

limited efficacy effective for-IgM limited efficacy, effective for-IgM

Splenectomy: refractory IgG dependent

chronic extravascular hemolysis chronic extravascular hemolysis

Immunosuppressive drugs:

cyclophosphamide 6 mercaptopurine 6 cyclophosphamide,6-mercaptopurine,6- thioguanine,azathioprine,cyclosporine A